Formic Acid → Azd-7624

Temperature

50 °C

To a slurry of benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate (15.0 g, 19.0 mmol), ammonium formate (4.9 g, 76.0 mmol) and 5% Pd/C (8.20 g, 3.8 mmol) in ethanol (150 mL) was charged water (6.8 mL, 379.8 mmol) and formic acid (1.49 mL, 388.0 mmol). The mixture was heated to 50° C. and held for 1 h before being cooled to 20° C. The mixture was filtered through a Celite pad, and the filter cake washed with ethanol (3×15 mL). The filtrates were combined and distilled (60° C. jacket temperature) to adjust the concentration of the solution to 2 rel. vol. with respect to the starting benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate. Isopropyl acetate (75 mL) was charged and the mixture cooled to 40° C. at 0.25° C./min. After seeding with the subtitle compound hydrobromide salt, the mixture was cooled further to 20° C. at 0.25° C./min. Isopropyl acetate (75 mL) was charged and the slurry cooled to 5° C. before being held for 1 h. The slurry was then filtered. The filter cake was washed with isopropyl acetate (15 mL) and dried under vacuum on the filter until de-liquoring was complete. The filter cake was then slurried in ethyl acetate (150 mL) and aq. sodium hydroxide (1 M, 150 mL) charged. The biphasic mixture was stirred at 20-25° C. until full dissolution was achieved (˜30 min). The phases were separated and the upper organic phase washed with aq. sodium hydroxide (1 M, 150 mL). The solution was then heated to 50° C. and distilled under reduced pressure to double the concentration (75 mL distillate removed). The solution was heated to 70° C. and heptane (56 mL) charged slowly. After seeding with the subtitle compound, the mixture was cooled to 25° C. at 0.25° C./min. Further heptane (19 mL) was charged slowly and the slurry cooled to 5° C. before being held for 1 h. The slurry was then filtered. The filter cake was washed with heptane (15 mL) and dried under vacuum at 40° C. to afford N-cyclopropyl-3-fluoro-4-methyl-5-[3-[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropylamino]-2-oxo-1(2H)-pyrazinyl]benzamide (6.0 g, 96.0% w/w).

1. temperaturebefore being cooled to 20° C
2. filtrationThe mixture was filtered through a Celite pad
3. washthe filter cake washed with ethanol (3×15 mL)
4. distillationdistilled (60° C. jacket temperature)
5. additionIsopropyl acetate (75 mL) was charged
6. temperaturethe mixture cooled to 40° C. at 0.25° C./min
7. temperaturethe mixture was cooled further to 20° C. at 0.25° C./min
8. additionIsopropyl acetate (75 mL) was charged
9. temperaturethe slurry cooled to 5° C.
10. waitbefore being held for 1 h
11. filtrationThe slurry was then filtered
12. washThe filter cake was washed with isopropyl acetate (15 mL)
13. customdried under vacuum on the
14. filtrationfilter until de-liquoring
15. additionaq. sodium hydroxide (1 M, 150 mL) charged
16. custom(˜30 min)
17. customThe phases were separated
18. washthe upper organic phase washed with aq. sodium hydroxide (1 M, 150 mL)
19. temperatureThe solution was then heated to 50° C.
20. distillationdistilled under reduced pressure
21. concentrationthe concentration (75 mL distillate removed)
22. temperatureThe solution was heated to 70° C.
23. additionheptane (56 mL) charged slowly
24. temperaturethe mixture was cooled to 25° C. at 0.25° C./min
25. additionFurther heptane (19 mL) was charged slowly
26. temperaturethe slurry cooled to 5° C.
27. waitbefore being held for 1 h
28. filtrationThe slurry was then filtered
29. washThe filter cake was washed with heptane (15 mL)
30. customdried under vacuum at 40° C.

ORD record

ord-9aa99c34852d4a6d9091146c9b054a46

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969350B2